Craniosynostosis, the premature fusion of calvarial sutures, is a common developmental anomaly that causes abnormal head shape. In moderate to severe cases, there is increase intracranial pressure and neurological sequelae, if not surgically treated. Craniosynostosis is a feature of as many as 50 genetic syndromes. Limb abnormalities, such as syndactyly and brachydactyly, are common associated features of these conditions. Crouzon, Jackson-Weiss, and Pfeiffer syndromes are autosomal dominant, craniosynostotic conditions with a wide variability of expression. We ascertained families with these conditions to study their chromosomes and/or DNA from established lymphoblastoid or fibroblast cell cultures. Fibroblast growth factor receptor 2 (FGFR2) mutations have been found in these conditions. We studied 39 cases with one of these three conditions for FGFR2 axon IlIa and llIc mutations. Eleven mutations were detected in 17 unrelated cases. Four mutations in either axon IlIa or axon llIc previously reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in axon IlIa in a Crouzon syndrome patient and the other in axon llIc in a Pfeiffer syndrome patient, were observed. The lafter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation, V359F, was detected in a family with one member with craniosynostosis and broad digits, diagnostic of Pfeiffer syndrome, and with two member with features consistent with Crouzon syndrome, craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders. We also studied a rare, autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, verrucous hyperplasia with hyperpigmentation of acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. We detected FGFR2 mutations in this condition, BeareStevenson cutis gyrata syndrome. Unlike the syndromes mentioned above, these mutations (Y375C and S372C) were found in axon 10 which contains the proximal region of or the transmembrane domain itself. These mutations presumably affect all FGFR2 isoforms, except soluble isoforms. Both the BEK (IIIc) and the keratinocyte growth factor receptor, KGFR (Illb) isoforms of FGFR2 formed by alternative splicing of exons lilc and lilb, respectively, would be affected because these exons are upstream of axon 10. The phenotype of Beare-Stevenson syndrome is consistent with the spatiotemporal expression patterns of both of these isoforms. The BEK isoform is expressed primarily in primordial bone and KGFR isoform predominantly in epithelial-derived tissues involved in the development of the skin.